Project Summary The goal of the proposed study is to investigate the influence of tau pathology on medial temporal lobe (MTL) function in normal aging. More specifically, we plan to examine how tau in the MTL influences hippocampal pattern separation, the process of disambiguating overlapping inputs into distinct outputs and how this process changes over time after consolidation and forgetting have occurred. Hippocampal pattern separation and its underlying behavioral phenotype mnemonic discrimination have been shown in both rodents and humans to be impaired in aging. Pattern separation provides a robust empirical framework for testing hippocampal function by manipulating mnemonic discrimination. To achieve these goals, we will use powerful high-resolution fMRI (1.8 mm isotropic) methods that are capable of dissociating subfield-specific signals, coupled with a parametric design manipulating interference of dynamic video stimuli rather than static, objects, words, or scenes, which are less ecologically valid. We will use this design to examine hippocampal pattern separation immediately and 24 hours later, once consolidation has occurred, in a group of cognitively normal older adults who have been studied with tau PET imaging. This is a highly innovative experiment that has never been previously accomplished. Successful completion of the project will shed light on the neural basis of memory consolidation in aging and the influence of tau pathology on hippocampal subfield activity, providing a better understanding of the network changes in cognitively normal aging and paving the way to improving dissociation of normal and pathological aging.